Methylene beta-ketoester monomers, methods for making methylene beta-ketoester monomers, polymerizable compositions and products formed therefrom

ABSTRACT

The present invention provides methylene beta-ketoester monomers, methods for producing the same, and compositions and products formed therefrom. In the method for producing the methylene beta-ketoesters of the invention, a beta-ketoester is reacted with a source of formaldehyde in a modified Knoevenagel reaction optionally in the presence of an acidic or basic catalyst, and optionally in the presence of an acidic or non-acidic solvent, to form reaction complex. The reaction complex may be an oligomeric complex. The reaction complex is subjected to further processing, which may be vaporization by contact with an energy transfer means in order to isolate the beta-ketoester monomer. The present invention further compositions and products formed from methylene beta-ketoester monomers of the invention, including monomer-based products (e.g., inks, adhesives, coatings, sealants or reactive molding) and polymer-based products (e.g., fibers, films, sheets, medical polymers, composite polymers and surfactants).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Provisional Patent Applications 61/549,092, filed Oct. 19, 2011; 61/549,104, filed Oct. 19, 2011; and 61/549,152, filed Oct. 19, 2011, the contents of which in their entirety are hereby incorporated herein by reference.

INCORPORATION BY REFERENCE

All documents cited or referenced herein and all documents cited or referenced in the herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated by reference, and may be employed in the practice of the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a new class of methylene beta-ketoester monomers, to methods of producing or synthesizing such monomers, and to the use and application of such monomers as commercial products and compositions, including, for example, monomer-based products (e.g., inks, adhesives, coatings, sealants or reactive molding) and polymer-based products (e.g., fibers, films, sheets, medical polymers, composite polymers and surfactants).

The new monomers relate to a platform of methylene beta-ketoester monomers having the general structural formula:

Products produced with such monomers include, for example, polymerizable compositions and polymers formed therefrom, e.g., inks, adhesives, coatings, sealants, reactive moldings, fibers, films, sheets, medical polymers, composite polymers and surfactants.

2. Background

Methylene malonate monomers have been disclosed for example in U.S. patent Nos.: U.S. Pat. Nos. 2,313,501; 2,330,033; 3,221,745; 3,523,097; 3,557,185; 3,758,550; 3,975,422; 4,049,698; 4,056,543; 4,160,864; 4,931,584; 5,142,098; 5,550,172; 6,106,807; 6,211,273; 6,245,933; 6,420,468; 6,440,461; 6,512,023; 6,610,078; 6,699,928; 6,750,298; and Patent Publications 2004/0076601; WO/2012/054616A2; WO2012/054633A2.

As described in certain of those publications, methylene malonates have the potential to form the basis of a large-scale platform of raw materials useful in a wide variety of chemical products.

It is envisioned that methylene beta-ketoester monomers and their associated monomeric and polymeric-based products would be useful in industrial, consumer, and medical applications. Specifically, methylene beta-ketoester monomers would provide a benefit over other monomers in that the incorporation of a ketone group adjacent to the active methylene group reduces the susceptibility of degradation of the monomer upon utilization or further functionalization. Indeed, unlike many other monomers, methylene beta-ketoester monomers and their products can be produced via sustainable routes as well as be designed to be environmentally benign, biologically benign and as such many of the products can be generally regarded as “green.”

Thus, there exists a need in the art for methods of synthesizing novel methylene beta-ketoester monomers, formulating novel polymerizable compositions, and providing polymer products based on this platform.

SUMMARY OF THE INVENTION

The purpose and advantages of the present invention will be set forth in and apparent from the description that follows. Additional advantages of the invention will be realized and attained by the methods and systems particularly pointed out in the written description and claims hereof, as well as from the appended drawings.

In one aspect, the invention provides a methylene beta-ketoester monomer having a structure:

wherein R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester;

or

wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In another aspect, the invention provides a method of making a methylene beta-ketoester monomer comprising:

-   -   a) reacting a beta-ketoester reactant having the structural         formula:

-   -    under suitable reaction conditions for sufficient time with a         source of formaldehyde, optionally in the presence of an acidic         or basic catalyst, and optionally in the presence of an acidic         or non-acidic solvent, to form a reaction complex; and     -   b) isolating a methylene beta-ketoester monomer from the         reaction complex, wherein the methylene beta-ketoester monomer         has the structural formula:

-   -    wherein each instance of R₁ and R₂ are independently C₁-C₁₅         alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl,         halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅         alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or         heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of         which may be optionally substituted by C₁-C₁₅ alkyl,         halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl),         heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅         alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl,         nitro, azido, cyano, acyloxy, carboxy, or ester;         or

wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In certain embodiments, the methods of the invention herein include the step of isolating the methylene beta-ketoester by:

-   -   i. contacting the reaction complex, or a portion thereof, with         an energy transfer means to produce a vapor phase including the         methylene beta-ketoester monomer; and     -   ii. collecting the methylene beta-ketoester monomer from the         vapor phase.

In other embodiments, the methods of the invention herein include isolating the methylene beta-ketoester by:

-   -   i. heating the reaction complex, or a portion thereof, to a         temperature between about 130° C. and about 300° C. to produce a         vapor phase including the methylene beta-ketoester monomer; and     -   ii. collecting the methylene beta-ketoester monomer from the         vapor phase.

In still other embodiments, the methods of the invention are performed under reaction conditions of:

a) an initiating temperature of between about 60° C. and about 130° C.;

b) atmospheric pressure.

In another aspect, the invention provides a method of preparing a methylene beta-ketoester monomer comprising:

a) reacting a beta-ketoester reactant having the structural formula:

-   -    under suitable reaction conditions for sufficient time with a         source of formaldehyde, optionally in the presence of an acidic         or basic catalyst, and optionally in the presence of an acidic         or non-acidic solvent, to form a reaction complex;     -   b) contacting the reaction complex, or a portion thereof, with         an energy transfer means at a temperature between about 150° C.         and about 300° C. to provide the reaction complex, or portion         thereof, as a vapor phase; and     -   c) isolating a methylene beta-ketoester monomer from the         reaction complex or portion thereof, wherein the methylene         beta-ketoester monomer has the structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester;

or

wherein each instance of R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In another aspect, the invention provides a polymerizable composition comprising a methylene beta-ketoester monomer of the invention.

In certain embodiments, the polymerizable composition is capable of bonding glass to a substrate in a time period of less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, or less than about 15 seconds.

In certain other embodiments, the polymerizable composition comprising a methylene beta-ketoester monomer further comprises at least one additive selected from the group consisting of an acidic stabilizer, a free radical stabilizer, a sequestering agent, a cure accelerator, a rheology modifier, a plasticizing agent, a thixotropic agents, a natural rubber, a synthetic rubbers, a filler agent and a reinforcing agent.

In another aspect, the invention provides an adhesive product comprising a methylene beta-ketoester monomer of the invention.

In certain embodiments, the adhesive products have a shelf life of at least one year.

In another aspect, the invention provides a polymer formed by polymerization of one or more methylene beta-ketoester monomers or a polymerizable composition thereof.

In certain embodiments, the polymers of the invention are useful as a sealant, a coating, a textile fiber, a water-treatment polymer, an ink carrier, a paint carrier, a packaging film, a molding, a medical polymer, a polymer film, a polymer fiber, or a polymer sheet.

In certain other embodiments, the polymers of the invention have repeat units of the formula:

wherein R and R′ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In another aspect, the invention provides an oligomeric complex prepared by reacting a beta-ketoester with a source of formaldehyde; optionally in the presence of heat transfer agent; optionally in the presence of an acidic or basic catalyst; and optionally in the presence of an acidic or non-acidic solvent. In certain embodiments, the oligomeric complex has between 2 and 12 repeat units having the structural formula:

wherein R and R′ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In still another aspect, the invention provides a methylene beta-ketoester monomer prepared according to the methods of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

So that those having ordinary skill in the art to which the subject invention pertains will more readily understand how to make and use the invention as described herein, preferred embodiments thereof will be described in detail below, with reference to the drawings, wherein:

FIGS. 1 and 2 depict NMR spectra demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 4,4-dimethyl-3-oxopentanoate and formaldehyde.

FIGS. 3 and 4 depict NMR spectra demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 3-oxo-3-phenylpropanoate with formaldehyde.

FIG. 5 depicts an NMR spectrum demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 3-oxo-hexanoate with formaldehyde.

FIG. 6 depicts an NMR spectrum demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 3-oxobutanoate with formaldehyde.

FIG. 7 depicts an NMR spectrum demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of methyl 3-oxobuanoate with formaldehyde.

FIG. 8 depicts an NMR spectrum demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 4-methyl-3-oxopentanoate with formaldehyde.

FIG. 9 depicts an NMR spectrum demonstrating evidence of a methylene beta-ketoester reaction product formed by the reaction of ethyl 3-oxopenanoate with formaldehyde.

DESCRIPTION OF THE INVENTION Overview

The present invention provides new and nonobvious improvements and modifications in the use and application of the Knoevenagel reaction in order to produce methylene beta-ketoester monomers:

Modified Knoevenagel Reaction

While the above reaction scheme shows a direct condensation reaction, it has been discovered that an intermediary species (oligomeric complex) may be formed in certain instances. The oligomeric complex may then be cracked to yield the monomer product. As those having skill in the art will appreciate, the reaction scheme may also yield side reactions and undesired products, and unreacted starting material from which the methylene beta-ketoester monomers are subsequently isolated.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

As used herein, the term “methylene beta-ketoester monomer” refers to a compound having the core formula —C(O)—C(═CH₂)—C(O)O—.

As used here, the term “beta-ketoester” refers to a compound having the core formula —C(O)—CH₂—C(O)O—.

As used herein, the term “monofunctional” refers to a methylene beta-ketoester or a beta-ketoester having only one core formula.

As used herein, the term “difunctional” refers to a methylene beta-ketoester or a beta-ketoester having two core formulas.

As used herein, the term “multifunctional” refers to a methylene beta-ketoester or a beta-ketoester having two or more core formulas. Thus the term multifunctional encompasses the term difunctional.

As used herein, the term “reaction complex” refers to the materials which result after reacting a beta-ketoester starting material with a source of formaldehyde. Such reaction complexes may comprise, without limitation, methylene beta-ketoester monomers, oligomeric complexes, irreversible complex impurities, starting materials, or latent acid-forming impurities.

As used herein, the term “reaction vessel” refers to any container in which the reactants, solvents, catalysts or other materials may be combined for reaction. Such reaction vessels can be made of any material known to one of skill in the art such as metal, ceramic or glass.

As used herein, the term “vapor phase” refers to a gaseous phase which may comprise, without limitation, vaporized methylene beta-ketoester monomer, vaporized starting materials; vaporized solvents, or vaporized impurities.

As used herein, the term “recovering” or “obtaining” or “isolating” refers to the removal of the monomer from the reaction mixture, vapor phase, or condensed vapor phase by one of the methods described herein, although the desired product may not be in a purified form. The term “crack” is also used to indicate depolymerization of an oligomeric complex. The desired methylene beta-ketoester monomer may be obtained by “cracking” an oligomeric complex found in the reaction complex.

As used herein, the term “sterically hindered” refers to a compound in which the size of groups within the molecule prevents chemical reactions that are observed in related smaller molecules.

As used herein, the terms “volatile” and “non-volatile” refers to a compound which is capable of evaporating readily at normal temperatures and pressures, in the case of volatile; or which is not capable of evaporating readily at normal temperatures and pressures, in the case of non-volatile.

As used herein, the term “energy transfer means” refers to a means which is capable of volatizing a reaction complex, usually by, but not limited to, rapidly heating the reaction complex to temperatures from about 150° C. to about 300° C. Such energy transfer means include, but are not limited to, heat transfer agents, heat transfer surfaces, lasers, and sources of radiation.

As used herein, the term “heat transfer agent” refers to a material which is capable of achieving a high temperature and transferring that temperature to a reaction mixture. Such heat transfer agents are typically able to reach temperatures from about 150° C. to about 300° C. and include, but are note limited to silica, silicone oil, mineral oil, a petroleum based heat transfer oil or a synthetic chemical based heat transfer oil. In certain embodiments, the heat transfer agent can be pre-formed reaction complex.

As used herein the term “pre-formed reaction complex” refers to a reaction complex as defined herein which is prepared by reacting step (a) as described herein in advance of the vaporization step (b). Such pre-formed reaction complexes can be formed up to a year, up to six months, up to 3 months, up to 1 month, up to 2 weeks, up to 1 week, up to 3 days, or up to 1 day in advance of the vaporization step (b). In such instances, the vaporization step (b) is performed on a newly prepared reaction complex. In certain aspects the pre-formed reaction complex can refer to an oligomeric complex as defined herein.

As used herein the term “substantial absence” as in “substantial absence of acidic solvent” refers to a reaction mixture comprising less than 1% by weight of the particular component as compared to the total reaction mixture. In certain embodiments, a “substantial absence” refers to less than 0.7%, less than 0.5%, less than 0.4% m less than 0.3%, less than 0.2% or less than 0.1% by weight of the of the particular component as compared to the total reaction mixture. In certain other embodiments, a “substantial absence” refers to less than 1.0%, less than 0.7%, less than 0.5%, less than 0.4% m less than 0.3%, less than 0.2% or less than 0.1% by volume of the of the particular component as compared to the total reaction mixture.

As used herein, the term “stabilized,” e.g., in the context of “stabilized” molecules of the invention or compositions comprising same, refers to the tendency of the molecules of the invention (or their compositions) to substantially not polymerize with time, to substantially not harden, form a gel, thicken, or otherwise increase in viscosity with time, and/or to substantially show minimal loss in cure speed (i.e., cure speed is maintained) with time.

As used herein, the term “shelf-life,” e.g., as in the context of the molecules of the invention having an improved “shelf-life,” refers to the molecules of the invention which are stabilized for a given period of time, e.g., 1 month, 6 months, or even 1 year or more.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

Methylene beta-ketoester monomers in accordance with the present invention may be made by a modified Knoevenagel condensation reaction of a beta-ketoester with formaldehyde under suitable reaction conditions. The general reaction scheme is provided below.

Modified Knoevenagel Reaction Methylene Beta-Ketoester Monomers

In one aspect, the invention provides a methylene beta-ketoester monomer having the structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester; or wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In certain embodiments, the invention provides a methylene beta-ketoester monomer having the structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₆ alkyl, halo-(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, heterocyclyl, heterocyclyl-(C₁-C₆ alkyl), aryl, aryl-(C1-C6 alkyl), heteroaryl or heteroaryl-(C₁-C₆ alkyl), each of which may be optionally substituted by halo or C₁-C₆ alkoxy.

In other embodiments, the invention provides a methylene beta-ketoester monomer having the structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₆ alkyl or aryl.

Reactants

The reaction for making methylene beta-ketoester monomers of the invention includes at least two basic reactants: a beta-ketoester precursor and a source of formaldehyde.

The methylene beta-ketoester precursors in accordance with exemplary embodiments disclosed herein include beta-ketoesters able to undergo a condensation reaction at the alpha carbon. Beta-ketoester precursors include, but are not limited to, molecules having the structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester;

or

wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

In certain other embodiments, the present invention contemplates the following specifically identified beta-ketoester precursors: ethyl 4,4-dimethyl-3-oxopentanoate, ethyl 3-oxo-3-phenylpropanoate, ethyl 3-oxohexanoate, ethyl 3-oxobutanoate, methyl 3-oxobuanoate, ethyl 4-methyl-3-oxopentanoate, and ethyl 3-oxopenanoate among others.

The beta-ketoester precursor may be derived or obtained from any source, including any commercial source, derived from nature, other compounds, synthesized by other processes, etc. In certain embodiments, the beta-ketoester precursors are obtained from “green” sources. For example, the beta-ketoester precursors can be derived from biological sources, such as via fermentation production systems whereby microorganisms generate the beta-ketoester precursors is direct metabolic by-products of fermentation—or whereby the microorganisms generate metabolic by-products of fermentation that can be then converted inexpensively to the desired beta-ketoester precursors. These fermentation production systems are well-known in the art and may utilize either—or both—microorganisms derived from nature or engineered microorganisms that are specifically designed to produce the desired beta-ketoester precursors products, e.g., recombinant or engineered Escherichia coli.

The beta-ketoester precursor is reacted with a source of formaldehyde. The methods of the invention also contemplate any suitable source of formaldehyde. For example, the formaldehyde may be synthesized, derived from another chemical species (e.g., paraformaldehyde), or obtained from nature or from some other suitable source. In certain embodiments, the formaldehyde is introduced in the form of a gas. Commercial sources of formaldehyde and paraformaldehyde are readily available, which may include, for example, trioxane and formalin (e.g., aqueous formaldehyde). The source of formaldehyde may be paraformaldehyde, formalin or gaseous formaldehyde. In certain embodiments, the formaldehyde is obtained from paraformaldehyde. In an exemplary embodiment, the source of formaldehyde is paraformaldehyde that is thermally degraded to formaldehyde in the reaction vessel. It is envisioned that other means of providing formaldehyde to the reaction vessel may be utilized, for example, a stream of gaseous formaldehyde.

Catalysts

In an certain embodiments, the methods of preparing the methylene beta-ketoester takes place in the presence of a suitable catalyst. However, it is envisioned that certain reactions may not required the presence of a catalyst.

In certain embodiments, the catalysts that may be used include, but are not limited to, basic catalysts such as potassium acetate, sodium acetate, zinc acetate, zinc diacetate dihydrate, aluminum acetate, calcium acetate, magnesium acetate, magnesium oxide, copper acetate, lithium acetate, aluminum oxide, or zinc oxide.

In further embodiments, the catalysts include, but are not limited to, acidic catalysts such as paratoluene sulfonic acid, dodecylbenzene sulfonic acid, boron trifluoride, zinc perchlorate, sulfated zirconium oxide, sulfated titanium oxide, lithium chloride, boron trifluoride etherate, ferric sulfate, zirconium oxychloride, cupric chloride, titanium tetrachloride, or zinc chloride.

Still other exemplary catalysts are heterogeneous catalysts. Still other exemplary catalysts are enzyme catalysts. An exemplary enzyme is Novozym® 435 available from Novozyme. Novozym 435 is an immobilized granulate, non-specific lipase particularly useful for ester production. Neutral catalysts can also include silica and other insoluble surface-active agents.

In still further embodiments, amphoteric catalysts can include, but are not limited to, aluminum oxide, aluminum acetate, zinc acetate, magnesium acetate, and zinc oxide.

In still other embodiments, the present inventors have surprisingly and unexpectedly found that no catalyst is required to conduct the synthesis reaction of the invention. Specifically, in this embodiment, the reaction can be conducted with all of the reactants added to the reaction vessel at the start of the reaction prior to adding heat. The source of formaldehyde in this embodiment is preferably solid paraformaldehyde, and is added along with the other reactants, including the malonic ester, prior to adding heat. This reaction surprisingly can be run rapidly and in a continuous mode and unexpectedly avoids the formation of—or substantially minimizes the formation of—deleterious side products, unwanted polymerization complexes and degradation of the monomer products.

Solvents

The present invention contemplates that the synthesis reaction include an acidic or non-acidic solvent, or optionally no solvent at all.

Non-acidic solvents can include, but are not limited to, tetrahydrofuran, chloroform, dichloromethane, toluene, heptane, ethyl acetate, n-butyl acetate, dibutyl ether and hexane.

Acidic solvents can include, but are not limited to acetic acid and propionic acid.

In certain embodiments, the acidic solvent is added just prior to recovery.

In certain other embodiment, optionally no solvent is needed. This zero-solvent approach will not only decrease the overall cost of production but will also help to lessen any negative impact on the environment caused by the methods of the invention, i.e., provides an environmentally-friendly approach to the synthesis of 2-methylene-1,3-disubstituted-propane-1,3-diones. An advantage of this condition is the avoidance or minimization of the formation of impurities, e.g., ketals and other latent acid-forming species.

In still other embodiments, the present inventors have surprisingly and unexpectedly found that the synthesis reaction of the invention may be conducted in the absence of both a solvent and a catalyst. Specifically, in this embodiment, the reaction can be conducted with all of the reactants added to the reaction vessel at the start of the reaction prior to adding heat and in the absence of a solvent. The source of formaldehyde in this embodiment is preferably solid paraformaldehyde, and is added along with the other reactants, including the malonic ester, prior to adding heat. This reaction surprisingly can be run rapidly and in a continuous mode and unexpectedly avoids the formation of—or substantially minimizes the formation of—deleterious side products, unwanted polymerization complexes and degradation of the monomer products.

Stabilization

Certain embodiments of the present invention provide monomers that are amenable to anionic polymerization. Therefore, to prevent unwanted polymerization and extend shelf life, certain exemplary embodiments include suitable acidic stabilizers, for example, trifluoromethane sulfonic acid, maleic acid, methane sulfonic acid, difluoro acetic acid, trichloroacetic acid, phosphoric acid, dichloroacetic acid, chlorodifluoro or like acid. Acidic stabilizers can include any material which can be added to the monomer or polymer compositions to extend shelf-life, e.g., by up to, for example, 1 year or more. Such acidic stabilizers may have a pKa in the range of, for example, between about −15 to about 5, or between about −15 to about 3, or between about −15 to about 1, or between −2 to about between about −2 to about 2, or between about 2 to about 5, or between about 3 to about 5.

Reaction Conditions

In certain embodiments of the present invention, the starting precursor is reacted with paraformaldehyde in the presence of a catalyst (e.g., zinc acetate dehydrate) at 60° C.-130° C. (e.g., 100° C.) for at least about 30 minutes. The resulting intermediate material (e.g., oligomeric complex) is then thermally depolymerized to the vinyl containing product by addition to a hot surface set from 150° C. to 270° C. The resulting crude monomer is then purified, for example by distillation, fractional distillation or other separation methods.

For a typical lab scale reaction: a 3-neck 250 mL round bottom reaction flask was equipped with an overhead stirrer, a heating mantle, and a temperature probe connected to a temperature controller. The reaction flask was adequately vented to the back of the hood to reduce the possibility of pressure build-up. The beta-ketoester (precursor), paraformaldehyde (1.8 equiv) and zinc acetate (0.001 equiv) were added to the reaction flask. The contents of the flask were mixed for approximately 2 minutes prior to the application of heat. After the initial mixing period the temperature controller was set to 100° C. The heterogeneous reaction mixture was allowed to heat with the temperature for dissolution and onset of exotherm being noted. Once a rapid increase in temperature was observed, heating was discontinued. Once the exotherm subsided, the heating mantle was immediately removed and the reaction mixture (herein “reaction complex”) was allowed to cool to room temperature to afford the oligomeric mixture.

To isolate the methylene beta-ketoester monomer from the reaction complex, a 4-neck suitable round bottom flask was equipped with a mechanical stirrer, heating mantle, a thermocouple connected to a temperature controller, an addition funnel, a Claisen adapter, and a vacuum adapter connected to a receiver one-neck round bottom flask which was placed in an ice-bath. The system was evacuated to low pressure (1-250 mmHg). The oligomeric mixture was added to the addition funnel. The reaction flask was then applied via the connected heating mantle to 150-270° C. Once the temperature inside the flask reached the desired range, a drop-wise addition of the oligomer (reaction complex) to reaction flask was started. The addition rate was maintained so that the set temperature was maintained in the desired range. After the addition was complete, the heating mantle was turned off and the system was allowed to cool to room temperature, at this point the system was opened to atmospheric pressure. An aliquot was then taken for analysis and the remaining cracked distillate was either distilled further via fractional distillation to improve purity or placed in a refrigerator.

This general reaction scheme was utilized to provide the examples provided herein. Due to the wide variety of example obtained, it is envisioned that this general reaction scheme can be utilized to provide a wide array of methylene beta-ketoester monomers as set forth herein. Further, it is envisioned that modifications can be made to this general reaction scheme in order to improve efficiencies and purity of the product obtained.

Methods of Synthesis

In another aspect, the invention provides a method of preparing methylene beta-ketoester monomers according to the reaction scheme disclosed herein.

In certain embodiments, the method for preparing the methylene beta-ketoester monomers comprises:

-   -   a) reacting a beta-ketoester reactant having the structural         formula:

-   -    under suitable reaction conditions for sufficient time with a         source of formaldehyde, optionally in the presence of an acidic         or basic catalyst, and optionally in the presence of an acidic         or non-acidic solvent, to form a reaction complex; and     -   b) isolating a methylene beta-ketoester monomer from the         reaction complex, wherein the methylene beta-ketoester monomer         has the structural formula:

wherein R₁ and R₂ are defined above.

In certain embodiments, the reaction may be initiated at temperatures between about 60° C. to about 130° C., at atmospheric pressure. It is contemplated that the reaction conditions may be modified depending on the source of formaldehyde. For example, when paraformaldehyde is utilized within the reaction vessel, the initial temperature must be high enough to make free formaldehyde available for the reaction. If another source of formaldehyde is utilized, those having skill in the art will appreciate that the reaction conditions may be modified accordingly. Exemplary sources include paraformaldehyde, formalin, trioxane, gaseous formaldehyde, or any reaction or process in which formaldehyde is liberated.

In other embodiments, the methylene beta-ketoester monomer may be isolated from the reaction complex by contacting the reaction complex, or a portion thereof, with an energy transfer means to produce a vapor phase including the methylene beta-ketoester monomer; and collecting the methylene beta-ketoester monomer from the vapor phase.

In still other embodiments, the methylene beta-ketoester monomer may be isolated from the reaction complex immediately, or the reaction complex may be stored, preferably refrigerated, until a later time. In an exemplary embodiment, the reaction complex is not acid stabilized prior to isolating the methylene beta-ketoester monomer.

In other embodiments, the reaction complex, or a portion thereof, may be heated to a vapor phase and condensed in order to isolate the methylene beta-ketoester monomer. The reaction complex may be heated to a temperature between about 130° C. and about 300° C.

In still other embodiments, the reaction complex, or a portion thereof, may come in contact with an energy transfer means in order to facilitate isolation of the monomer. In an exemplary embodiment, the reaction complex, or portion thereof, may be vaporized in a very short time, for example less than 15 minutes, preferably less than 1 minute, more preferably less than 30 seconds, and less than 1 second. Certain exemplary embodiments contemplate vaporizing the reaction complex in a continuous manner as it is formed during the reaction step.

Exemplary energy transfer means include a heat transfer agent, a heat exchanger, a laser, microwave energy, sonic energy, electromagnetic energy, and a source of radiation, or any combination thereof. The energy transfer means operates to quickly vaporize the reaction complex (or portion thereof) to permit isolation of the monomer product. For example, an oligomeric complex may be formed, and the energy transfer means is utilized to “crack” or depolymerize the oligomer to allow isolation of the monomer. In certain embodiments, the oligomeric complex may include oligomers of 2-12 units able to provide monomer product upon crack.

In certain exemplary embodiments, the heat transfer agent is a heated inert gas, one or more metal beads, one or more glass beads, one or more porcelain beads, sand, silica, silicone oil, mineral oil, a petroleum based heat transfer oil, a synthetic chemical based heat transfer oil, or a pre-formed portion of the reaction complex.

In certain other embodiments, the heat exchanger is a shell and tube heat exchanger, a plate heat exchanger, and adiabatic wheel heat exchanger, a finned pipe heat exchanger, a plate fin heat exchanger, or a scraped surface heat exchanger.

In still other embodiments, the vapor phase of the reaction complex is condensed, and the condensate is subject to one or more further separation processes. For example, the separation process may include any of simple distillation, fractional distillation, flash distillation, steam distillation, vacuum distillation, short path distillation, thin-film distillation, reactive distillation, pervaporation, extractive distillation, flash evaporation, rotary evaporation, liquid/liquid extraction, centrifuging, or any combination thereof, and other techniques known to those having skill in the art.

Compositions

The methylene beta-ketoester monomers of the invention can be incorporated into any number of compositions and products including but not limited to reactive monomer-based compositions, reactive oligomer-based compositions and reactive polymer-based compositions.

Exemplary compositions can be analyzed by placing a drop of a monomer composition on a substrate (for example a glass slide or 4″×1″ polycarbonate sample). Another glass slide or piece of polycarbonate is pressed on top over the monomer-covered area. The time is then immediately recorded from pressing the top-slide till the two slides are bonded tightly. In such embodiments, the exemplary composition is capable of bonding glass to a substrate in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds or less than about 15 seconds. Similarly, the exemplary composition is capable of bonding polycarbonate to a substrate in less than about 90 seconds, less than about 60 seconds, less than about 45 seconds or less than about 30 seconds.

Alternatively, exemplary compositions can be analyzed by mixing 0.5 ml of monomer with 0.3 ml of 3% tertiary butyl ammonium fluoride (TBAF) in Dibutyl Phthalate solution. The time is recorded from adding the TBAF solution till the mixture become solid with vigorous stiffing or mixing. In such embodiments, said composition solidifies upon addition of 3% tertiary butyl ammonium fluoride (TBAF) in Dibutyl Phthalate solution in less than about 15 seconds, less than about 10 seconds, or less than about 7 seconds.

Alternatively still, the exemplary compositions can be analyzed by placing 0.5 ml of monomer into a test tube and cap with a cork stopper and keeping the test tubes containing monomers at 25° C., or in ovens at 55° C. or 82° C. In each case the storage stability test is performed at atmospheric pressure. Time is recorded when the monomer became a gel or solid. In such embodiments, said composition remains stable at 25° C. and at atmospheric pressure for more than 10 days, more than 15 days, more than 20 days, more than 25 days or more than 30 days. Similarly, said composition remains stable at 82° C. and at atmospheric pressure for more than about 2 hours, more than about 3 hours, or more than about 4 hours.

Exemplary compositions include, but are not limited to an adhesive, a coating, a sealant, a composite, or a surfactant.

Additionally polymer products include, but are not limited to, a sealant, a thermal barrier coating, a textile fiber, a water-treatment polymer, an ink carrier, a paint carrier, a packaging film, a molding, a medical polymer, a polymer film, a polymer fiber or a polymer sheet.

In each case, the exemplary compositions may be formulated to include one or more materials to extend the shelf-life as well as control the onset of cure of the materials. In certain embodiments, the compositions are formulated such that the composition is stable for at least 1 month, or for at least 2 months, or for at least 3 months, or for at least 4 months, or for at least 5 months, or for at least 5-10 months, or for at least 10-20 months, or for at least 20-30 months. Preferably, the adhesive composition comprising the methylene beta-ketoester monomers or other commercial compositions or products, are stable for at least one year.

Such formulation materials include acidic stabilizer, volatile acid stabilizers, acidic gases, free radical stabilizers, sequestering agents, cure accelerators and rheology modifiers.

Exemplary embodiments contemplate any suitable acidic stabilizer known in the art, including, for example, trifluoromethane sulfonic acid, maleic acid, methane sulfonic acid, difluoro acetic acid, trichloroacetic acid, phosphoric acid, dichloroacetic acid, chlorodifluoro or like acid. Acidic stabilizers can include any material which can be added to the monomer or polymer compositions to extend shelf-life, e.g., by up to, for example, 1 year or more. Such acidic stabilizers may have a pKa in the range of, for example, between about −15 to about 5, or between about −15 to about 3, or between about −15 to about 1, or between −2 to about between about −2 to about 2, or between about 2 to about 5, or between about 3 to about 5.

Volatile acid stabilizers include any material which can be added to the monomer or polymer compositions to extend shelf-life and stabilize the vapor phase above the composition upon storage, e.g., acidic gases. Such volatile acid stabilizers may have a boiling point, for example, less than about 200° C.; less than about 170° C.; or less than about 130° C.

Acidic gases include any gaseous material which can be added to the monomer or polymer compositions to extend shelf-life and stabilize the vapor phase above the composition upon storage. Such acid gases can include, but are not limited to, SO₂ or BF₃.

For each of these acidic stabilizing materials, such acidic stabilizer can be present in a concentration of about 0.1 ppm to about 100 ppm; about 0.1 ppm to about 25 ppm; or about 0.1 ppm to about 15 ppm.

Free radical stabilizers can include any material capable of stabilizing or inhibiting free radical polymerization of the material upon standing. In one embodiment, the free radical stabilizers are phenolic free radical stabilizers such as, HQ (hydroquinone), MEHQ (methyl-hydroquinone), BHT (butylated hydroxtoluene) and BHA (butylated hydroxyanisole). In certain embodiments, the free radical stabilizers are present in a concentration of 0.1 ppm to 10,000 ppm; 0.1 ppm to 3000 ppm; or 0.1 ppm to 1500 ppm. In certain other embodiments, particularly where a free radical or ultraviolet cure will be utilized, the free radical stabilizers are present in a concentration of 0.1 ppm to 1000 ppm; 0.1 ppm to 300 ppm; or 0.1 ppm to 150 ppm.

Sequestering agents include any material capable of enhancing the bonding of materials containing acid salts such as paper or wood. Such sequestering agents include, but are not limited to crown ethers, silyl crowns, calixarenes and polyethylene glycols. Sequestering agents also enhance the utility of surface accelerators that are acid salts applied to surfaces to control the rate of cure of the materials.

Cure accelerators include any material capable of speeding the rate of cure of the methylene beta-ketoester monomers. Cure accelerators also include any material capable of speeding the cure through volume of the applied composition. Such cure accelerators include but are not limited to sodium or potassium acetate; acrylic, maleic or other acid salts of sodium, potassium lithium copper and cobalt; salts such as tetrabutyl ammonium fluoride, chloride, or hydroxide; or chemically basic materials such as amines and amides, or salts of polymer bond acids, benzoate salts, 2,4-pentanedionate salts, sorbate salts, or propionate salts. Such cure accelerators can be added directly to the exemplary compositions or applied to the material to be bonded prior to addition of the composition.

Rheology modifiers include any material which can modify the viscosity of the exemplary compositions as well as thixotropic properties for greater utility in certain applications. Rheology modifiers include, but are not limited to, hydroxyethylcellulose, ethyl hydroxyethylcellulose, methylcellulose, polymeric thickeners, pyrogenic silica or a combination thereof.

In certain embodiments, the exemplary compositions may include tougheners. Such tougheners include, but are not limited to, acrylic rubbers; polyester urethanes; ethylene-vinyl acetates; fluorinated rubbers; isoprene-acrylonitrile polymers; chlorosulfonated polyethylenes; homopolymers of polyvinyl acetate; and reaction products of the combination of ethylene, methyl acrylate and monomers having carboxylic acid cure sites, which once formed are then substantially free of processing aids and anti-oxidants; and combinations thereof. In certain embodiments, the tougheners include those disclosed in U.S. Pat. No. 4,440,910 (O′Connor), directed to rubber toughened cyanoacrylate compositions through the use of certain organic polymers as toughening additives that are elastomeric, i.e., rubbery, in nature, such as acrylic rubbers; polyester urethanes; ethylene-vinyl acetates; fluorinated rubbers; isoprene-acrylonitrile polymers; chlorosulfonated polyethylenes; and homopolymers of polyvinyl acetate. In certain embodiments, the toughener is an elastomeric polymer which is a copolymer of methyl acrylate and ethylene, manufactured by DuPont, under the name of VAMAC, such as VAMAC N123 and VAMAC B-124. VAMAC N123 and VAMAC B-124 are reported by DuPont to be a master batch of ethylene/acrylic elastomer. In other embodiments, the toughener may be the DuPont materials called VAMAC B-124, N123, VAMAC G, VAMAC VMX 1012 or VCD 6200. In other instances, the toughener may be a rubber toughening component having (a) reaction products of the combination of ethylene, methyl acrylate and monomers having carboxylic acid cure sites, (b) dipolymers of ethylene and methyl acrylate, and combinations of (a) and (b), which once the reaction products and/or dipolymers are formed are then substantially free of processing aids, such as the release agents octadecyl amine (reported by DuPont to be available commercially from Akzo Nobel under the tradename ARMEEN 18D), complex organic phosphate esters (reported by DuPont to be available commercially from R.T. Vanderbilt Co., Inc. under the tradename VANFRE VAM), stearic acid and/or polyethylene glycol ether wax, and anti-oxidants, such as substituted diphenyl amine (reported by DuPont to be available commercially from Uniroyal Chemical under the tradename NAUGARD 445). Commercial examples of such rubber tougheners include VAMAC VMX 1012 and VCD 6200 rubbers, and these may be used too.

The exemplary compositions containing methylene beta-ketoester monomer may also optionally include other additives, such as plasticizing agents, thixotropic agents, natural or synthetic rubbers, filler agents, and reinforcing agents, etc. Such additives are well known to those skilled in the art.

The exemplary compositions containing methylene beta-ketoester monomer may optionally include at least one plasticizing agent that imparts flexibility to the polymer formed from the methylene beta-ketoester monomer. The plasticizing agent preferably contains little or no moisture and should not significantly affect the stability or polymerization of the monomer. Such plasticizers are useful in polymerized compositions to be used in any application in which flexibility of the adhesive or polymer product is desirable.

Examples of suitable plasticizers include, without limitation, acetyl tributyl citrate, dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl)phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate, and mixtures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate. In embodiments, suitable plasticizers include polymeric plasticizers, such as polyethylene glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and polyester adipates.

The addition of plasticizing agents in amounts less than about 60 weight %, or less than about 50 weight %, or less than about 30 weight %, or less than about 10 weight %, or less than about 5 weight %, or less than about 1 weight % or less, provides increased film strength (e.g., toughness) of the polymerized monomer over polymerized monomers not having plasticizing agents.

The exemplary compositions containing methylene beta-ketoester monomer may also optionally include at least one thixotropic agent, i.e., the property of exhibiting a high fluidity during deformation by force of a sprayer, roller or trowel, but losing the fluidity when left at rest. Suitable thixotropic agents are known to the skilled artisan and include, but are not limited to, silica gels such as those treated with a silyl isocyanate. Examples of suitable thixotropic agents are disclosed in, for example, U.S. Pat. Nos. 4,720,513 or 4,510,273, the disclosures of which are hereby incorporated in their entireties.

The exemplary compositions containing methylene beta-ketoester monomer may also optionally include at least one natural or synthetic rubber to impart impact resistance, which is preferable especially for industrial compositions of the present invention. Suitable rubbers are known to the skilled artisan. Such rubbers include, but are not limited to, dienes, styrenes, acrylonitriles, and mixtures thereof. Examples of suitable rubbers are disclosed in, for example, U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of which are hereby incorporated in their entireties.

The exemplary compositions containing methylene beta-ketoester monomer may also optionally comprise one or more other reinforcing agents (e.g., fibrous reinforcements) other than natural or synthetic rubber to impart impact resistance and/or to impart structural strength or to provide shape or form. Examples of such agents are well known in the art. Examples of suitable fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils. The compositions may also contain colorants such as dyes, pigments, and pigment dyes. Examples of suitable colorants include 6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+C Yellow No. 6); 9-(o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one monohydrate (FD+C Red No. 3); and 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid (FD+C Blue No. 2), wherein the suitable colorant should not destabilize the monomer.

The exemplary compositions containing methylene beta-ketoester monomer may also optionally include at least one thickening agent. Suitable thickeners include, for example, polycyanoacrylates, polylactic acid, poly-1,4-dioxa-2-one, polyoxalates, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene. Examples of alkyl methacrylates and acrylates are poly(2-ethylhexyl methacrylate) and poly(2-ethylhexyl acrylate), also poly(butylmethacrylate) and poly(butylacrylate), also copolymers of various acrylate and methacrylate monomers, such as poly(butylmethacrylate-co-methylacrylate).

To improve the cohesive strength of adhesives formed from the compositions containing methylene beta-ketoester monomer, difunctional monomeric cross-linking agents may be added to the monomer compositions of this invention. Such crosslinking agents are known. U.S. Pat. No. 3,940,362 to Overhults, which is hereby incorporated in its entirety by reference, discloses such crosslinking agents.

Other compositions and additives contemplated herein, include additional stabilizers, accelerators, plasticizers, fillers, opacifiers, inhibitors, thixotrophy conferring agents, dyes, fluorescence markers, thermal degradation reducers, adhesion promoters, thermal resistance conferring agents and combinations thereof, and the like, some of which are exemplified by U.S. Pat. Nos. 5,624,669; 5,582,834; 5,575,997; 5,514,371; 5,514,372; 5,312,864 and 5,259,835, the disclosures of all of which are hereby incorporated in their entirety by reference.

Depending on whether the composition is a monomer-based composition (e.g., inks, adhesives, coatings, sealants or reactive molding) or a polymer-based composition (e.g., fibers, films, sheets, medical polymers, composite polymers and surfactants), one having ordinary skill in the art will have the knowledge and skill by which to formulate such compositions and/or products without undue experimentation having suitable amounts, levels and combinations of the above types of additives and components.

Additionally, polymerizable compositions may be formulated to include additives such as acidic stabilizers, a free radical stabilizers, a sequestering agents, a cure accelerators, rheology modifiers, a plasticizing agents, a thixotropic agents, natural rubbers, synthetic rubbers, filler agents, reinforcing agents and the like. Such additives are provided at levels sufficient to achieve the desired results which can readily be determined by those having skill in the art.

For certain exemplary embodiments, an acidic stabilizer is present in a concentration of about 0.1 ppm to about 100 ppm, about 0.1 ppm to about 25 ppm, or about 0.1 ppm to about 15 ppm, by weight of the composition.

For certain exemplary embodiments, a free radical stabilizer is present in a concentration selected from about 0.1 ppm to about 10000 ppm, about 0.1 ppm to about 3000 ppm, about 0.1 ppm to 1500 ppm, about 0.1 ppm to about 1000 ppm, about 0.1 ppm to about 300 ppm, or about 0.1 ppm to about 150 ppm, by weight of the composition.

For certain exemplary embodiments, a sequestering agent, such as a crown ether, a silyl crown, a calixarene, a polyethylene glycol, or a combination thereof may be utilized.

For certain exemplary embodiments, a cure accelerator, such as sodium acetate, potassium acetate, tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium hydroxide, a benzoate salt, a 2,4-pentanedionate salt, a sorbate salt, and a propionate salt, may be utilized.

For certain exemplary embodiments, a rheology modifier, such as hydroxyethylcellulose, ethyl hydroxyethylcellulose, methylcellulose, a polymeric thickener, and pyrogenic silica, may be utilized.

Exemplary polymerizable compositions are stable at 25° C. and at atmospheric pressure for more than 10 days, more than 15 days, more than 20 days, more than 25 days, or more than 30 days. Certain exemplary embodiments may exhibit a shelf life of up to one year, or up to two years. Certain exemplary embodiments may be tested for stability at elevated temperature, e.g., 82° C., at atmospheric pressure. Certain exemplary embodiments may exhibit elevated temperature stability for more than 2 hours.

Certain exemplary embodiments disclosed herein relate to polymers and polymer products formed by polymerization of the polymerizable compositions comprising the methylene beta-ketoester monomers.

Polymers and polymer products envisioned include coatings, paints, fibers, composites, textile fibers, water-treatment polymers, ink carriers, paint carriers, packaging films, moldings, medical polymers, polymer films, polymer fibers, polymer sheets, and the like. As discussed earlier, the methylene beta-ketoester monomers are capable of supporting a vast array of products due to the activity of the methylene group and the ability to vary the functional groups R, R′ as shown in the structure of the repeating unit:

wherein R and R′ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.

Oligomeric Complex Products

The reaction of the precursor beta-ketoester with the source of formaldehyde may result in an oligomeric complex which is subsequently cracked to obtain the desired methylene beta-ketoester monomer. Certain oligomeric complexes are capable of being efficiently vaporized or “cracked” into high purity monomers of 2-methylene-1,3-disubstituted-propane-1,3-dione by rapid vaporization as described herein.

As such, the invention provides an oligomeric complex prepared by reacting a 1,3-disubstituted-propane-1,3-dione with a source of formaldehyde; optionally in the presence of heat transfer agent; optionally in the presence of an acidic or basic catalyst; and optionally in the presence of an acidic or non-acidic solvent. In certain embodiments, the oligomeric complex comprises between 2 and 12 repeat units that are able to yield monomer upon cracking

The invention further provides an oligomeric complex prepared by reacting a 1,3-disubstituted-propane-1,3-dione with a source of formaldehyde in a substantial absence of acidic solvent; optionally in the presence of heat transfer agent; optionally in the presence of an acidic or basic catalyst; and optionally in the presence of a non-acidic solvent. In certain embodiments, the substantial absence of acidic solvent represents less than 1.0%, less than 0.5%, less than 0.2% or less than 0.1% by weight acidic solvent as compared to the total composition of the reaction mixture.

EXAMPLES

The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

Analytical Methods

The structures of monomers of this invention were confirmed using one or more of the following procedures.

NMR

Samples were diluted in deuterated chloroform prior to 1H NMR spectroscopy at 300 MHz (Bruker). A more concentrated sample was also prepared in a solution of 0.01 M Cr(III) acetoacetonate in deuterated chloroform and was analyzed by quantitative 13C NMR spectroscopy at 75 MHz. Samples were not purified.

Abbreviations and Acronyms

A comprehensive list of the abbreviations used by organic chemists of ordinary skill in the art appears in The ACS Style Guide (third edition) or the Guidelines for Authors for the Journal of Organic Chemistry. The abbreviations contained in said lists, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughout this disclosure, they have the following meanings:

atm atmosphere

br s broad singlet

C Celsius

d doublet

dd doublet of doublets

MM substituted 3-methylene-2,4-pentanebeta-ketoester

HQ hydroquinone

GC-MS Gas Chromatography-Mass Spectroscopy

g gram

h hour, hours

¹H NMR proton nuclear magnetic resonance

J coupling constant (NMR spectroscopy)

L liter

M mol·L⁻¹ (molar)

m multiplet

MHz megahertz

min minute, minutes

mL milliliter

mM millimolar

mol mole

MS mass spectrum, mass spectroscopy

m/z mass-to-charge ratio

N equivalents·L⁻¹ (normal)

NMR Nuclear Magnetic Resonance

pH negative logarithm of hydrogen ion concentration

q quartet

rt room temperature

s singlet

t triplet

RB, RBF round bottom flask

The following concrete examples were made in accordance with the reaction scheme set forth above.

Example 1 Reaction of ethyl 4,4-dimethyl-3-oxopentanoate and formaldehyde

A 250 mL round bottom flask was equipped with a heating mantle, an overhead stirrer equipped with a teflon paddle, a thermocouple and an outlet adapter with attached rubber tubing vented to the back of the hood. The round bottom flask was placed on a heating mantle. A 50 g sample of ethyl pivaloylacetate (i.e., 4,4-dimethyl-3-oxopentanoate), 4.8 g of paraformaldehyde and 0.06 g of zinc acetate were added to the round bottom flask to form a heterogeneous mixture. After 2 minutes of mixing the temperature was set to 100° C. and heating was started. After 5 minutes of reaction time at a temperature of 55° C., the mixture began to clarify. After an additional 30 seconds an exotherm was observed at an approximate temperature of 65.5° C. At this point heating was stopped and the reaction was allowed to proceed. A maximum temperature of 122.1° C. was attained after 8 minutes. The crude product was allowed to cool to room temperature at which time a viscous light yellow liquid was obtained. An aliquot of this material was analyzed by 1H and 13C NMR. This oligomeric material was then depolymerized/cracked as detailed below.

A 4-neck 250 mL round bottom flask was fitted with a mechanical stirrer, an addition funnel, a thermocouple attached to a temperature controller, a Claisen distillation head, vacuum adapter connected to a one-neck 100 mL round bottom flask placed in an ice bath. The system was evacuated to 100 mmHg after which heat was then applied via a heating mantle. When the set temperature reached 190° C., the oligomer was slowly added to the hot cracking flask. The resulting crude monomer was simultaneously cracked and distilled to the receiving flask. During the distillation phase an average head temperature of 155° C. was observed. After the addition was completed, the heat source was turned off and the system was allowed to cool to room temperature. The crude pale green monomer was then analyzed by ¹H and ¹³C NMR.

The following monomer was obtained.

FIGS. 1 and 2 show the ¹H, ¹³C, and DEPT-135 NMR spectra of the isolation step (“crack”) in this reaction. Peaks at 5.6 and 6.3 ppm in the ¹H and 126 ppm in the ¹³C NMR spectrum correspond to the geminal CH₂ species and the quaternary peak at 142 ppm are consistent with the product.

Example 2 Reaction of ethyl 3-oxo-3-phenylpropanoate with formaldehyde

The reaction scheme disclosed herein was performed using ethyl 3-oxo-3-phenylpropanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIGS. 3 and 4 show peaks at 6.1 and 6.7 ppm in the ¹H NMR spectrum and a peak at 131 ppm in the ¹³C NMR spectrum corresponding to the geminal CH₂ peak and a quaternary peak at 142 ppm, which are consistent with the product.

Example 3 Reaction of ethyl 3-oxohexanoate with formaldehyde

The reaction scheme disclosed herein was performed using ethyl 3-oxohexanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIG. 5 shows the ¹H NMR spectrum. Peaks at 6.25 and 6.35 ppm are consistent with the geminal CH₂ of the product.

Example 4 Reaction of ethyl 3-oxobutanoate with formaldehyde

The reaction scheme disclosed herein was performed using ethyl 3-oxobutanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIG. 6 shows the ¹H NMR spectrum. The two small peaks at 6.4 and 6.5 ppm are consistent with the geminal CH₂ of the product.

Example 5 Reaction of methyl 3-oxobuanoate with formaldehyde

The reaction scheme disclosed herein was performed using methyl 3-oxobuanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIG. 7 shows the ¹H NMR spectrum. The peaks at 6.4 and 6.5 ppm are consistent with the geminal CH₂ of the product

Example 6 Reaction of ethyl 4-methyl-3-oxopentanoate with formaldehyde

The reaction scheme disclosed herein was performed using ethyl 4-methyl-3-oxopentanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIG. 8 shows the ¹H NMR spectrum. The peaks at 6.15 and 6.35 ppm are consistent with the geminal CH₂ of the product.

Example 7 Reaction of ethyl 3-oxopenanoate with formaldehyde

The reaction scheme disclosed herein was performed using ethyl 3-oxopenanoate and formaldehyde (obtained from paraformaldehyde). The following monomer was obtained.

FIG. 9 shows the ¹H NMR spectrum. The peaks at 6.3 and 6.4 ppm are consistent with the geminal CH₂ of the product.

Example 8 Additional Examples

The reaction scheme disclosed herein is performed using an appropriate beta-ketoester reactant and a source of formaldehyde to obtain the following monomers.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by this invention. 

1-58. (canceled)
 59. A methylene beta-ketoester monomer comprising at least one core formula represented by —C(O)—C(CH2)-C(O)—O—.
 60. The methylene beta-ketoester monomer according to claim 59 represented by the following structural formula:

wherein each instance of R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester; or wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.
 61. The methylene beta-ketoester monomer according to claim 60 having a structural formula selected from the group consisting of:


62. The methylene beta-ketoester monomer according to claim 60 having a structural formula selected from the group consisting of:


63. A polymerizable composition including at least one methylene beta-ketoester monomer according to claim
 60. 64. The polymerizable composition according to claim 63 further comprising a stabilizing amount of at least one stabilizer selected from the group consisting of: an acidic stabilizer, a vapor phase stabilizer, and a free radical stabilizer.
 65. The polymerizable composition according to claim 64 wherein the at least one stabilizer includes the acidic stabilizer selected from trifluoromethane sulfonic acid, maleic acid, methane sulfonic acid, difluoro acetic acid, trichloroacetic acid, phosphoric acid, dichloroacetic acid, and chlorodifluoro acid.
 66. The polymerizable composition according to claim 63 wherein the at least one stabilizer includes the vapor phase stabilizer selected from hydroquinone, methyl hydroquinone, butylated hydroxytoluene, butylated hydroxyanisole.
 67. The methylene beta-ketoester monomer according to claim 60 being formed as a reaction product of a beta-ketoester represented by R₁—C(O)—C—C(O)—O—R₂, and a source of formaldehyde.
 68. A method of making a methylene beta-ketoester monomer comprising: a) reacting a beta-ketoester reactant having the structural formula:

 with a source of formaldehyde, optionally in the presence of an acidic or basic catalyst, and optionally in the presence of an acidic or non-acidic solvent, to form a reaction complex; and b) isolating a methylene beta-ketoester monomer from the reaction complex, wherein the

 methylene beta-ketoester monomer has the structural formula: wherein each instance of R₁ and R₂ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester; or wherein R₁ and R₂ are taken together with the atoms to which they are bound to form a 5-7 membered heterocyclic ring which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.
 69. The method according to claim 68 wherein in step (b), isolating the methylene beta-ketoester monomer comprises: i. contacting the reaction complex, or a portion thereof, with an energy transfer means to produce a vapor phase including the methylene beta-ketoester monomer; and ii. collecting the methylene beta-ketoester monomer from the vapor phase.
 70. The method according to claim 68, wherein in step (b), isolating the methylene beta-ketoester monomer comprises: i. heating the reaction complex, or a portion thereof, to a temperature between about 130° C. and about 300° C. to produce a vapor phase including the methylene beta-ketoester monomer; and ii. collecting the methylene beta-ketoester monomer from the vapor phase.
 71. The method according to claim 68 wherein the reaction conditions include: a) an initiating temperature of between about 60° C. and about 130° C.; and b) atmospheric pressure.
 72. The method according to claim 68 wherein the source of formaldehyde includes paraformaldehyde, formalin, tiroxane or gaseous formaldehyde, or any combination thereof.
 73. The method according to claim 68 wherein isolating the methylene beta-ketoester monomer includes condensing the vapor phase to a condensate and thereafter subjecting the condensate to a separation process selected from simple distillation, fractional distillation, flash distillation, steam distillation, vacuum distillation, short path distillation, thin-film distillation, reactive distillation, pervaporation, extractive distillation, flash evaporation, rotary evaporation, liquid/liquid extraction, centrifuging, or any combination thereof
 74. The method according to claim 68, wherein the reaction complex comprises one or more oligomeric complexes capable of forming the methylene beta-ketoester monomer upon cracking.
 75. A polymer having repeat units of the formula:

wherein R and R′ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cyclo alkyl, halo-(C₃-C₆ cyclo alkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester.
 76. A polymer product comprising the polymer according to claim
 75. 77. The polymer product according to claim 76 selected from the group consisting of a coating, a paint, a fiber, a composite, a textile fiber, a water-treatment polymer, an ink carrier, a paint carrier, a packaging film, a molding, a medical polymer, a polymer film, and a polymer sheet.
 78. An oligomeric complex prepared by reacting a beta-ketoester reactant with a source of formaldehyde; optionally in the presence of a heat transfer agent; optionally in the presence of an acidic or basic catalyst; and optionally in the presence of an acidic or non-acidic solvent.
 79. The oligomeric complex according to claim 78, having between 2 and 12 repeat units having the structural formula:

wherein R and R′ are independently C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C1-C15 alkyl), heteroaryl or heteroaryl-(C₁-C₁₅ alkyl), or alkoxy-(C1-15 alkyl), each of which may be optionally substituted by C₁-C₁₅ alkyl, halo-(C₁-C₁₅ alkyl), C₃-C₆ cycloalkyl, halo-(C₃-C₆ cycloalkyl), heterocyclyl, heterocyclyl-(C₁-C₁₅ alkyl), aryl, aryl-(C₁-C₁₅ alkyl), heteroaryl, C₁-C₁₅ alkoxy, C₁-C₁₅ alkylthio, hydroxyl, nitro, azido, cyano, acyloxy, carboxy, or ester. 